The present invention relates to a novel process for preparing pyrrole ester compounds which are key intermediate in the preparation of farnesyl transferase inhibitors, an anti-cancer agent (see: Ko, J. S. et al., WO 9928315). Horner-Emmons reaction of aldehyde compounds provides the corresponding xcex1,xcex2-unsaturated esters, which without any separation and/or purification steps, are treated with toluenesulfonylmethylisocyanate (TosMIC: hereinafter referred to as xe2x80x98TosMICxe2x80x99) in the presence of base to give pyrrole esters in one-pot fashion.
The most typical method for the synthesis of 3-substituted-4-pyrrole ester compound is through the cyclization reaction of an isonitrile compound with an electrophilic xcex1,xcex2-unsaturated compound, as depicted in the following Reaction Scheme 1. As isonitrile part, TosMIC is the most well known reagent (van Leusen, A. M. et.al. Teiahedron Leit. 1972, 52, 5337.). 
in which
R1 and R2 independently of one another represent C1-C4-alkyl.
Recently BetMIC (Katrizky, A. R. et.al. Heterocycles, 1997, 44, 67.) of the following formula showing a similar reactivity to TosMIC has been developed. 
Thereafter, the same researcher has developed a new method as depicted in the following Reaction Scheme 2. TosMIC is reacted with a carbonyl compound in the presence of a base and POCl3(phosphorous oxychloride) in sequence to give an xcex1,xcex2-unsaturated isonitrile compound, which is then reacted with an activated nucleophile to give a pyrrole compound (van Leusen, A. M. et.al. J Org. Chem. 1992, 57, 2245.). 
in which
R represents alkyl, allyl, or aryl, and
E represents an electron-withdrawing group.
As known in the previous arts, the general synthesis of 3-substituted-4-pyrrole ester contains two discrete stages. The first stage is the preparation and purification of xcex1,xcex2-unsaturated compound and the second stage is the cyclization reaction of the purified xcex1,xcex2-unsaturated compound with TosMIC in the presence of base. However, since the conventional method requires purification step after the preparation of xcex1,xcex2-unsaturated compound, it is inevitable to efflux the reaction solvent as waste unless it is recycled. To remove the efflux of waste solvent and increase the efficiency of the process, it is proposed to run the two reactions in the same solvent as one-pot fashion.
Under the technical background as explained above, the present inventors have investigated extensively on the eradication of the waste solvent problem and the increase of the efficiency of the process for the purpose of mass production of pyrrole ester. As a result, we have come up with the present invention by combining the two stages of the pyrrole synthesis into one-pot/one stage process. Therefore, the pyrrole ester is obtained in high purity and in environmentally friendly manner.
The object of the present invention is to provide a process for preparing a desired pyrrole ester derivative represented by the following formula (1): 
in which
R represents alkyl, allyl, or aryl, and
R1 represents C1-C4-alkyl, by reacting an aldehyde compound represented by the following formula (2): 
in which R is defined as previously described, with a trialkylphosphonoacetate represented by the following formula (3): 
in which R1 is defined as previously described, in an inert solvent in the presence of an alkali metal alkoxide base in an amount of 1 to 1.5 molar equivalent with respect to the compound of formula (2) to give an xcex1,xcex2-unsaturated ester compound represented by the following formula (4): 
in which R and R1 are defined as previously described, and subsequently by adding TosMIC and the same base as used in the previous step in an amount of 1 to 1.5 molar equivalent with respect to the compound of formula (2).
The process according to the present invention is depicted in the following Reaction Scheme 3 
In the process of the present invention, it is very important to use the alkali metal alkoxide base in an amount of 1 to 1.5 molar equivalents with respect to the compound of formula (2). If the amount of base is deviated from the defined range, the reaction to prepare the unsaturated ester compound of formula (4) is not proceeded cleanly. As a result, the object of the present invention to react the unsaturated ester compound directly in the next step in the same reaction system without being separated cannot be achieved. As the base which can be used for such a purpose, alkali metal methoxide, -ethoxide, -t-butoxide, -t-pentoxide, etc., preferably sodium- or potassium-t-butoxide or -t-pentoxide can be used. Though the reaction is well proceeded by using the base in an amount of 1 to 1.5 molar equivalents, however, 1 to 1.3 molar equivalent thereof may be sufficient to exhaust the aldehyde compound. Further, an excess base may cause hydrolysis in the subsequent separation step of layers, it is preferable to use the base in an amount of 1 to 1.3 molar equivalent in order to minimize such a hydrolysis reaction.
Any inert solvent which does not adversely affect to the reaction can be used in the process according to the present invention, but tetrahydrofuran, dimethoxyethane, toluene or mixtures thereof is preferably used.
After the process for preparing the compound of formula (4) is completed, TosMIC and the same base as used in the previous reaction step were added and stirred until the xcex1,xcex2-unsaturated ester is completely removed to produce the pyrrole ester compound of formula (1). In this reaction, TosMIC is added in an amount of 1 to 1.3 molar equivalent with respect to the compound of formula (2) and the base is added in an amount fallen under the same range as mentioned in the previous step of preparing the compound of formula (4). Then, the reaction solution is quenched with water and extracted with a suitable extracting solvent which is not miscible with water at temperature of 40 to 90xc2x0 C. (if a high yield is desired, 60 to 90xc2x0 C. is preferable). The organic layer was separated and stirred at room temperature, and the formed precipitate is filtered to give the desired compound of formula (1) in a pure state. The solvent is not always required to remove before carrying out the extraction. But, in case of tetrahydrofuran or dimethoxyethane is used as the reaction solvent, since they are well miscible with water, it is required to be removed by distillation. Therefore, the increase of yield can be expected if the solvent is removed in advance by distillation under reduced pressure before the extraction. As the extracting solvent for this purpose, toluene or n-butyl acetate can be preferably used. Particularly, when sodium-t-pentoxide is used as the base, since this base is well soluble in the preferable extracting solvent toluene, the trouble to have to use an extracting solvent different from the reaction solvent may be saved.
The reaction for preparing the compound of formula (4) is proceeded at temperature ranging from xe2x88x9220 to 40xc2x0 C., preferably 10 to 25xc2x0 C. on a satisfactory level. Also, the process for producing the desired pyrrole ester derivative of formula (1) from the compound of formula (4) thus obtained is suitably carried out at temperature ranging from 0 to 40xc2x0 C.
Contrary to the prior arts, after the unsaturated ester compound of formula (4) is produced, it directly reacts with TosMIC without any separation or purification, in the present invention to afford the pyrrole ester. Thus, reduction of the waste solvent and enhancement of the efficiency of the process is obvious and provides great advantage particularly when the process is applied on an industrial production.